Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

被引:19
作者
Tudpor, Kukiat [1 ]
Lainez, Sergio [1 ]
Kwakernaak, Arjan J. [4 ]
Kovalevskaya, Nadezda V. [1 ,2 ]
Verkaart, Sjoerd [1 ]
van Genesen, Siebe [3 ]
van der Kemp, Annemiete [1 ]
Navis, Gerjan [4 ]
Bindels, Rene J. M. [1 ]
Hoenderop, Joost G. J. [1 ]
机构
[1] Radboud Univ Nijmegen Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Physiol, Nijmegen, Netherlands
[2] Radboud Univ Nijmegen Med Ctr, Inst Mol & Mat, Dept Prot Biophys, Nijmegen, Netherlands
[3] Radboud Univ Nijmegen Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Biomol Chem, Nijmegen, Netherlands
[4] Univ Groningen, Univ Med Ctr Groningen, Div Nephrol, Dept Internal Med, Groningen, Netherlands
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2012年 / 23卷 / 11期
关键词
EPITHELIAL NA+ CHANNELS; CA2+ CHANNEL; THROMBIN RECEPTOR; KINASE-C; ACTIVATION; NEPHROCALCINOSIS; DESENSITIZATION; IDENTIFICATION; GROWTH; SITES;
D O I
10.1681/ASN.2011111126
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Urinary proteins that leak through the abnormal glomerulus in nephrotic syndrome may affect tubular transport by interacting with membrane transporters on the luminal side of tubular epithelial cells. Patients with nephrotic syndrome can develop nephrocalcinosis, which animal models suggest may develop from impaired transcellular Ca2+ reabsorption via TRPV5 in the distal convoluted tubule (DCT). In nephrotic-range proteinuria, filtered plasminogen reaches the luminal side of DCT, where it is cleaved into active plasmin by urokinase. In this study, we found that plasmin purified from the urine of patients with nephrotic-range proteinuria inhibits Ca2+ uptake in TRPV5-expressing human embryonic kidney 293 cells through the activation of protease-activated receptor-1 (PAR-1). Preincubation with a plasmin inhibitor, a PAR-1 antagonist, or a protein kinase C (PKC) inhibitor abolished the effect of plasmin on TRPV5. In addition, ablation of the PKC phosphorylation site S144 rendered TRPV5 resistant to the action of plasmin. Patch-clamp experiments showed that a decreased TRPV5 pore size and a reduced open probability accompany the plasmin-mediated reduction in Ca2+ uptake. Furthermore, high-resolution nuclear magnetic resonance spectroscopy demonstrated specific interactions between calmodulin and residues 133-154 of the N-terminus of TRPV5 for both wild-type and phosphorylated (S144pS) peptides. In summary, PAR-1 activation by plasmin induces PKC-mediated phosphorylation of TRPV5, thereby altering calmodulin-TRPV5 binding, resulting in decreased channel activity. These results indicate that urinary plasmin could contribute to the downstream effects of proteinuria on the tubulointerstitium by negatively modulating TRPV5.
引用
收藏
页码:1824 / 1834
页数:11
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